Ocular treatment compositions and methods of use thereof

ABSTRACT

A substantially water-free ocular treatment composition including about 20% to about 45% beeswax and about 20% to about 45% jojoba oil. The composition can include at least one ingredient selected from the group consisting of shea butter, caprylic/capric triglyceride, phospholipid, sodium hyaluronate, and coconut oil. The composition can be administered to a patient to improve the functionality of the tear film and decrease dry eye symptoms. The composition can be a semi-solid at room temperature and can liquefy when contacted with the skin at body temperature.

FIELD

The present subject matter relates to a composition for protectingocular surfaces, and more particularly, to a composition for protectingocular surfaces comprising a mixture of beeswax and jojoba oil.

BACKGROUND

Dry eye disease, also referred to as ocular surface disease, is anophthalmic condition that typically results when the tear film isinadequate to protect the ocular surface. The tear film has three layersanchored to the corneal epithelium of the ocular surface: the lipidlayer, the aqueous layer, and the mucin layer. Although the three layersare described as separate layers, it is generally accepted that there issome mixing of the various layers, particularly the mucin and aqueouslayers.

The outermost layer is the lipid layer, reportedly varying in thicknessfrom about 30 nm to about 150 nm. The lipid layer protects theunderlying layers of the tear film and the corneal nociceptors of theneurosensory system. The aqueous layer is the middle layer and isreported to be about 2-4 microns thick. The mucin layer, the innermostlayer, is anchored to and directly protects the epithelium of the ocularsurfaces. The mucin layer is reported to be about 0.5-1.5 microns thick.The lipid layer primarily functions to retard evaporation of the aqueouslayer. Dry eye disease can occur when the lipid layer fails toadequately minimize tear film evaporation and maintain homeostasis.

The lipids forming the lipid layer are primarily secreted by themeibomian glands. For the eye to achieve an optimal ocular surfaceprotective system, the meibomian glands must function at a level ofefficacy to provide adequate lipid levels to form and maintain the lipidlayer, thereby minimizing tear film evaporation and maintaininghomeostasis. Meibomian glands discharge lipids (sebum) onto the lidmargin upon completion of a blink. In addition to facilitating secretionof lipids and other chemical constituents of the tear film, blinkingspreads the tear film over the ocular surface, polishes the planar tearfilm for optimal vision, and acts as a pump system to remove a portionof the tear film through the nasal lacrimal system when needed. Themovement of the lids and eyelashes also acts as a defense againstintruding foreign material.

Meibomian gland dysfunction is an obstructive condition of the ducts ofthe meibomian glands that prevents the glands from discharging theirlipid liquid secretions (sebum) to maintain the tear film and protectthe ocular surface. Meibomian gland dysfunction is the leading cause ofdry eye disease throughout the world. Properly functioning meibomianglands discharge sebum continuously primarily during the waking hours toprovide a continuous feed system to maintain the tear film and protectthe ocular surface. However, in almost all dry eye conditions, themeibomian glands do not work well and/or underperform.

In recent times, there has been a significant rise in occurrences of dryeye disease. One of the main causes of this rise is an overall increasein screen time. People staring at a screen for extended periods of timehave a tendency to blink less. Reduced blinking leads to inadequatelevels of lipid secretion and, consequently, a lipid layer that isinadequate to retard evaporation of the aqueous layer of the tear film.

An insufficient lipid layer also fails to protect the nociceptors of theneurosensory system from stimulus. The nociceptors are primarilyprotected by the tear film during waking hours. If the patient's tearfilm is not adequate, environmental factors, such as a wind current, maycause tearing. An optimally functioning tear film may protect ocularsurfaces from winds that are up to about 4-5 miles per hour. When thetear film becomes compromised and the nociceptors are not protected,winds at this speed can cause the nociceptors to set off a cascade ofneurosensory stimulation, resulting in symptoms of discomfort,inflammation, and mild to severe or even disabling sequelae, dependingupon the individual situation.

Many conventional dry eye treatments fail to adequately protect theocular surfaces and neurosensory systems. For example, many treatmentshave been directed to palliative measures, such as suppressinginflammation with steroids. Other treatments, such as lubricant eyedrops, are severely limited by the minimal capacity of the eye to retainonly about 1-3 microliters of additional substances from externalsources. For example, a standard eye drop is about 30-50 microliters,while the eye has a capacity to retain only about 2-5 microliters. As aresult, over 90% of a standard eyedrop overflows on to the face. Thus,much of the eyedrop is lost upon dispensing and any remaining amountstays in the eye for a very short time (minutes to at most an hour)before evaporating. These treatments fail to address the need to providea reservoir to facilitate protection of the ocular surface andneurosensory systems for at least the majority of waking hours.

Accordingly, a composition for protecting the ocular tear film isneeded.

SUMMARY

A composition for ocular treatment as described herein can be asubstantially water-free composition including about 20% to about 45%beeswax and about 20% to about 45% jojoba oil. The composition caninclude at least one further ingredient/excipient. Such furtheringredients/excipients can include any or all those selected from thegroup consisting of shea butter, caprylic/capric triglyceride,phospholipid, hyaluronic acid, and coconut oil, alone or in anycombination of two or more thereof. The composition can be administeredto a patient to decrease evaporation of moisture from the tear film andincrease the thickness of the tear film. The composition can be asemi-solid at room temperature and can liquefy when contacted with theskin at body temperature. The composition can be administered to apatient for treating or preventing dry eye disease, meibomian glanddysfunction, or eyelid infection or inflammation. The composition canreplicate or be adjunctive to the function and efficacy of thoseingredients supplied by the secretory systems of an optimallyfunctioning eye.

The composition can be administered to the patient by rubbing thecomposition on an external eyelid surface of a patient to create an oilyreservoir thereon. The external eyelid surface can include the outerskin of the upper eyelid, the outer skin of the lower eyelid, the eyelidmargin, and the eyelashes, or combinations of 2 or more thereof. Thecomposition deposited on the external eyelid surface can move to theocular surface in minute portions at a time, primarily by blinking. Inthis manner, a continuous feed of the composition is supplied to theocular surface.

The composition can help prevent evaporation from the aqueous layer andprovide a thicker tear film. The composition can provide an extendedperiod of protection for the ocular surface and neurosensory systemswithout causing blurring of vision. For example, the composition canprotect the ocular surfaces for about 10 hours to about 24 hours perday. The composition can protect the nociceptors from winds ranging fromabout 1 MPH to about 10-20 MPH. The composition can replicate or beadjunctive to the function and efficacy of those ingredients supplied bythe secretory systems of an optimally functioning eye to protect theocular surfaces for extended periods of time to withstand thecontemporary demands and stresses of prolonged electronic screen viewingand other visual activities associated with reduced blinking.

It should be noted the compositions described herein may be regulated asa cosmetic, drug, device, medicament, or combinations thereof.

DETAILED DESCRIPTION Definitions

The following definitions are provided for the purpose of understandingthe present subject matter and for constructing the appended patentclaims.

The phrase “ocular surface” refers to the eye anatomy that can beobserved if the upper lid is raised and the lower lid lowered, includingthe inner surfaces of both upper and lower eyelids upon their eversion,but without surgical intervention, and the non-visible surfaces withinthe eye cavity.

The term “ophthalmic” refers to relating to the eye and its diseases.

The phrase “tear film” refers to the complex mixture of substancessecreted from multiple sources, including the lacrimal gland, theaccessory lacrimal glands, the meibomian glands, and the goblet cells,on to the ocular surface. The tear film resides on the ocular surface.

The phrase “lipid layer” refers to the outermost layer of the tear film.Typically, the lipid layer of the tear film will vary in thickness fromabout 30 nm to about 150 nm. The lipid layer primarily functions toretard evaporation at the lipid layer—air interface. The lipids formingthe lipid layer are primarily secreted by the meibomian glands.

The phrase “aqueous layer” refers to the middle layer of the tear filmand is the thickest layer of the tear film. Typically, the aqueous layerof the tear film will be about 2 microns to about 4 microns thick.

The phrase “mucin layer”, also termed mucous, mucus, or glycocalyx,refers to the innermost layer of the tear film that is typicallyanchored to and protects the epithelium of the ocular surface.Typically, the mucin layer of the tear film is about 0.5 microns toabout 1.5 microns thick.

The term “homeostasis” refers to the process of maintaining a stable,relatively constant function of the eye.

The phrase “substantially water-free” is intended to mean that thecomposition comprises the water content which would nominally be presentin the ingredients. No water is added to the formulation. Total moisturecontent would be less than 5%, and more likely less than 1% on a weightbasis.

The phrase “external eyelid surface” as used herein can include theouter skin of the upper eyelid, the outer skin of the lower eyelid, theeyelid margin, and the eyelashes, or combinations of 2 or more thereof.The composition deposited on the external eyelid surface can move to theocular surface in minute portions at a time, primarily by blinking.

The phrase “eyelid margin” refers to the edge of the eyelid. Unlike theskin of the external eyelid surface, which includes keratinizednon-wetting epithelium, the eyelid margin includes non-keratinizedwetting epithelium. The junction of the wetting and non-wettingepithelium is termed the mucocutaneous junction. The orifices of themeibomian glands are located slightly in front of the mucocutaneousjunction. The meibomian glands discharge their oil product (sebum) on tothe keratinized wetting epithelium. A row of eyelashes extends along thefront of the eyelid margin.

The phrase “meibomian glands” refers to “oil glands” located in thetarsal plates of the eyelids. The meibomian glands discharge an oilysubstance, sometimes referred to as the sebum or meibomian lipids,through their orifices on to the eyelid margin, primarily upon blinking.The oily substance is then moved from the eyelid margin by eye movementsand eyelid actions to the lipid layer where it provides tearstabilization and serves as a barrier protector of the aqueous layerunderneath.

The meibomian lipids form a thin, smooth film. The thickness andprobably the composition of the film influence the rate of evaporation.The melting range of the meibomian lipids ensures sufficient fluidityfor delivery to the tear film from the lid margin reservoirs, while thefilm itself may exhibit a higher viscosity at the cooler temperature ofthe ocular surface. The factors governing lipid film formation duringthe blink are not fully understood, but one view is that the polarlipids, interacting with the aqueous sub-phase of the tear film, spreadin advance of the non-polar components, which form the bulk of the film.The meibomian lipids stabilize the tear film by lowering its freeenergy; they carry water into the film during its formation and interactwith lipid-binding proteins in the aqueous phase, such as tearlipocalin. The lipocalins, complexed with other tear components, mayalso contribute to the high, non-Newtonian viscosity of the tear filmand its low surface tension, features which are essential for tear filmstability. Formation of the lipid film is a complex process. The lipidlayer comes to a stop after completion of the blink and remainsrelatively immobile until it is compressed in the down-phase of theblink that follows. Then, it either retains its structure in a series ofsubsequent blinks or is re-constituted after mixing with the reservoirlipids. Delivery of meibomian lipid to the marginal reservoirs is mainlythe result of continuous secretion, under neural and hormonal control,supplemented by lid action. The reservoirs provide a hydrophobic barrierto tear overspill and to contamination by skin lipids which mightdestabilize the tear film. They also provide a portion of the route formeibomian gland secretion to join the lipid layer.

The phrase “jojoba oil” refers to jojoba oil, jojoba wax, combinationsthereof and/or derivatives thereof derived from the jojoba plant. Theterms “jojoba oil” and “jojoba wax” are often used interchangeablybecause the wax visually appears to be a mobile oil, but as a wax it iscomposed almost entirely (˜97%) of mono-esters of long-chain fatty acidsand alcohols (wax ester), accompanied by only a tiny fraction oftriglyceride esters. One such substance has been described by the PCPC(Personal Care Products Counsel) International Cosmetic IngredientDictionary and Handbook as Simmondsia chinensis (Jojoba) Seed Oil.Jojoba oil is non-aqueous and is typically used as a skin conditioningagent, an occlusive, and a hair conditioning agent.

The phrase “shea butter” refers to a triglyceride derived from the treeShorea stepnoptera. It is rich in C18 unsaturated carbon length chainlengths. One such substance has been described by the PCPC (PersonalCare Products Counsel) International Cosmetic Ingredient Dictionary andHandbook as Butyrospermum parkii (Shea) Butter. Shea butter isnon-aqueous and is typically used as a skin conditioning agent, anocclusive, and a viscosity increasing agent.

The phrase “coconut oil” refers to a triglyceride derived predominatelyfrom the seed of Cocos nucifera. It is rich in carbon lengths below C18,and particularly C12 (lauric). One such substance has been described bythe PCPC (Personal Care Products Counsel) International CosmeticIngredient Dictionary and Handbook as Cocos nucifera (Coconut) Oil.

The phrase “caprylic/capric triglyceride” is a mixed triglyceridederived predominately from kernel oils, e.g., coconut oil, palm kerneloil, and babassu oil. One such substance has been described by the PCPC(Personal Care Products Counsel) International Cosmetic IngredientDictionary and Handbook as caprylic/capric triglyceride. Caprylic/caprictriglyceride is typically used as a skin conditioning agent and anocclusive.

The term “liquefy” refers to a process to soften, melt, disperse, orotherwise cause a loss of viscosity in a solid or semi-solidcomposition, rendering the composition more fluid.

The term “phospholipid” refers to an ingredient including aphospholipid. A preferred, non-limiting phospholipid containingingredient useful in the present compositions is lecithin. Lecithin istypically used as a skin conditioning agent, an emulsifying agent, and asurfactant. Other phospholipid-containing ingredients known to those ofordinary skill in the art, such as those described in the resourcesbelow, are further contemplated as useful in the present compositions.The phospholipids can include at least one of neutral, anionic andcationic phospholipids. Other phospholipids well known to those of skillin the art as useful in topical and ophthalmic compositions are furthercontemplated as useful in the present compositions, such as thosedescribed in The Merck Index, Thirteenth Edition, Budavari et al., Eds.,Merck & Co., Inc., Rahway, N.J. (2001); the PCPC (Personal Care ProductsCounsel) International Cosmetic Ingredient Dictionary and Handbook, OnLine Infobase (2021); and the “Inactive Ingredient Guide”, U.S. Food andDrug Administration (FDA) Center for Drug Evaluation and Research (CDER)Office of Management, January 2021, the contents of which are herebyincorporated by reference in their entirety.

The term “beeswax” refers to Cera alba, White Beeswax, Yellow Beeswax,or Apis mellifera, and is listed in pharmaceutical pharmacopoeias andcosmetic ingredient dictionaries such as those listed above. Beeswax isnonaqueous, includes about 15% free fatty acids, 15% hydrocarbon resins,and the balance esters. It is rich in carbon chain lengths greater thanC18 and is typically used as a skin conditioning agent and a viscosityincreasing agent-non-aqueous.

The phrase “degradation products” refers to the compositions produced bya change in the physical or chemical properties of one or more of thefunctional ingredients of the composition used according to the presentmethods. Degradation may result in the change in the physicalappearance, physical attribute, or a loss of functionality of the oculartreatment composition. A product or composition which maintainssufficient physical appearance or chemical stability to render itfunctional for its intended use is considered storage stable.

The terms “patient” or “subject,” are used interchangeably herein torefer to a mammal or animal, including but not limited to a human being.

It is noted that, as used in this specification and the appended claims,the singular forms “a”, “an”, and “the” include plural references unlessthe context clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which the presently described subject matter pertains.

Where a range of values is provided, for example, concentration ranges,percentage ranges, or ratio ranges, it is understood that eachintervening value, to the tenth of the unit of the lower limit, unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the described subject matter. Theupper and lower limits of these smaller ranges may independently beincluded in the smaller ranges, and such embodiments are alsoencompassed within the described subject matter, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either or both ofthose included limits are also included in the described subject matter.

Throughout the application, descriptions of various embodiments use“comprising” language. However, it will be understood by one of skill inthe art, that in some specific instances, an embodiment canalternatively be described using the language “consisting essentiallyof” or “consisting of”.

For purposes of better understanding the present teachings and in no waylimiting the scope of the teachings, unless otherwise indicated, allnumbers expressing quantities, percentages or proportions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about”.Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the sought desiredproperties. At the very least, each numerical parameter should at leastbe construed in light of the number of reported significant digits andby applying ordinary rounding techniques.

The ocular treatment composition as described herein can be asubstantially water-free composition including a first wax having afirst melting temperature and a second wax having a second meltingtemperature different from the first melting temperature. Additionalwaxes may optionally be included in the composition as needed. A ratioof the first wax to the second wax can range from about 1:1 to about 2:1in the composition. In an embodiment, a ratio of the first wax to thesecond wax can be about 1:1 in the composition. In an embodiment, thecomposition can include one or more oils, emollients, antimicrobials,antioxidants, and/or thickening agents. In an embodiment, thecomposition can include at least one ingredient selected from the groupconsisting of caprylic/capric triglyceride, phospholipid, coconut oil,and hyaluronic acid. In an embodiment, a combined concentration of thefirst wax and the second wax in the composition can range from about 40%to about 90%. In an embodiment, the composition can include from about0% to about 16% shea butter. In an embodiment, the composition caninclude from about 5% to about 15% caprylic/capric triglyceride. In anembodiment, the composition can include from about 0.1% to about 2%phospholipid. In an embodiment, the composition can include 0.01% toabout 0.1% sodium hyaluronate. In an embodiment, the composition caninclude from about 0% to about 16% coconut oil.

The composition can be administered to a patient to decrease evaporationfrom the tear film and increase the thickness of the tear film. Thecomposition can be non-fluid at room temperature and liquefy when incontact with surfaces with elevated temperatures, such as the skin atbody temperatures.

The compositions as described herein can liquefy upon application to thepatient's external eyelid surface to ensure sufficient fluidity fordelivery to the tear film from the application area, such as the eyelidmargin, while the film itself may exhibit a higher viscosity at thecooler temperature of the ocular surface. The factors governing filmformation are complex and may vary somewhat within and across patients.Naturally occurring ocular polar compositions interact during blinkingwith the aqueous sub-phase of the tear film, spread in advance of thenon-polar components, which form the bulk of the tear film. The oculartreatment composition becomes dispersed in situ with the meibomianlipids. A dynamic process of blinking, mixing, reservoir release andreplenishment, dispersion with naturally occurring substances in theeye, and formation of a mixture of chemical substances from natural andexternal sources ensues, resulting in the development of a complex filmwhich protects and restores the functional ocular surface.

In an embodiment, the first melting temperature can be greater than 50°C. In an embodiment, the second melting temperature can be less than 20°C. In an embodiment, the first melting temperature can range from about62° C. to about 64° C. In an embodiment, the second melting temperaturecan range from about 5° C. to about 11° C. In an embodiment, the firstwax is beeswax. In an embodiment, the second wax is jojoba oil.Preferably, the first melting temperature is from beeswax and the secondis from jojoba oil.

In an embodiment, the composition includes a third wax having a thirdmelting temperature. The third melting temperature can be different fromthe first and second melting temperatures. The third melting temperaturecan range from about 31° C. to about 37° C. In an embodiment, the thirdwax is shea butter.

In an embodiment, the composition can include hyaluronic acid, a salt,ester or complex thereof. In an embodiment, the hyaluronic acid includessodium hyaluronate. Sodium hyaluronate is typically used as a skinconditioning agent and a humectant.

In an embodiment, the composition can include one or more oils.Exemplary oils suitable for use in the composition include, but are notlimited to, sunflower oil, coconut oil, castor oil, vegetable oil, cornoil, canola oil, soybean oil, olive oil, babassu oil, avocado oil,apricot oil, meadowfoam seed oil, macadamia seed oil, oat kernel oil,palm seed oil, safflower oil, sandalwood oil, sesame oil, sunflower oil,almond oil, wheat germ oil, cranberry seed oil, daikon seed oil, andcombinations thereof. In an embodiment, the composition includes coconutoil (Cocos nucifera). Coconut oil is typically used as an occlusive anda hair conditioning agent. Other oils well known to those of skill inthe art as useful in topical and ophthalmic compositions are furthercontemplated as useful in the present compositions, such as thosedescribed in The Merck Index, Thirteenth Edition, Budavari et al., Eds.,Merck & Co., Inc., Rahway, N.J. (2001); the PCPC (Personal Care ProductsCounsel) International Cosmetic Ingredient Dictionary and Handbook, OnLine Infobase (2021); and the “Inactive Ingredient Guide”, U.S. Food andDrug Administration (FDA) Center for Drug Evaluation and Research (CDER)Office of Management, January 2021, the contents of which are herebyincorporated by reference in their entirety.

The composition can include at least one of an antimicrobialpreservative and an antioxidant for improving storage stability. Thecomposition can include at least one additional component selected fromthe group consisting of a therapeutic agent, a coloring agent, apreservative, a pH control agent, an antioxidant, a viscosity controlagent, and an odor control agent.

A concentration of the first and second waxes in the composition can begreater than a combined concentration of other ingredients in thecomposition. In an embodiment, the composition can include at leastabout 20%, e.g., about 25%, about 30%, or about 35% beeswax. In anembodiment, the composition can include at least about 20%, e.g., about25%, about 30%, or about 33% beeswax. In an embodiment, the combinedconcentration of the first and second waxes in the composition isgreater than 40%.

In an embodiment, the ocular treatment composition can include about 37%to about 43% beeswax; about 35% to about 41% jojoba oil; and at leastone ingredient selected from the group consisting of shea butter,caprylic/capric triglyceride, phospholipid, sodium hyaluronate, andcoconut oil. In an embodiment, the composition can include at leastabout 5% caprylic/capric triglyceride, at least about 0.1% phospholipid,from about 0% to about 0.05% sodium hyaluronate, from about 0% to about16% coconut oil, and from about 0% to about 16% shea butter. Forexample, the composition can include from about 5% to about 12%caprylic/capric triglyceride, from about 0.1% to about 2% phospholipid,from about 0% to about 0.05% sodium hyaluronate, from about 0% to about16% coconut oil, and from about 0% to about 16% shea butter

The composition can be administered to the external eyelid surface of apatient for treating or preventing a broad spectrum of ocular disordersincluding dry eye conditions and dry eye disease; meibomian glanddysfunction; other eyelid margin disorders and diseases; eyelid andperiorbital dermatitis; inflammation; infection; and symptoms associatedwith these maladies. Symptoms of these diseases include pain,discomfort, itching, dryness, grittiness, burning, crusting, wateryeyes, vague sensations of eyes and/or lids, and/or eye fatigue. Itshould be understood that the composition can treat or prevent ormitigate essentially all dry eye conditions and diseases, includingtemporary conditions resulting from the stresses of prolonged electronicscreen viewing as well as severe dry eye disease resulting from systemicdiseases, such as rheumatoid arthritis and diabetes. The external eyelidsurface can include the outer skin of the upper eyelid, the outer skinof the lower eyelid, the eyelid margin, the eyelashes, or combinationsof two or more thereof.

A method of treating an ophthalmologic condition can includeadministering a semi-solid composition to the external eyelid surface ofthe patient. The semi-solid composition can be the ocular treatmentcomposition described herein, or any other suitable semi-solid oculartreatment composition. When the semi-solid composition contacts theexternal eyelid surface, at least a portion of the composition liquefiesto provide an oily film. The oily film deposited on the external eyelidsurface can move to the ocular surface in minute amounts over time. Theprimary mechanisms for moving the liquefied composition from theexternal eyelid surface to the tear film and the lipid layer areblinking, lid actions, and eye movements. In this manner, application ofa semi-solid composition to the external eyelid surface can provide acontinuous feed system to the ocular surface. The blinking can bevoluntary or involuntary.

The composition can start to be delivered to the tear film afterapplication. Portions of the composition can remain on the externaleyelid surface, e.g., to serve as a reservoir, for delivery to the eyefor preferably up to 24 hours. Once deposited on the tear film, thecomposition does not cause blurring, stinging or other adversereactions. The composition can both prevent evaporation of the tear filmand provide a thicker tear film to protect the nociceptors. For example,the composition can protect the nociceptors from winds of about 1 MPH toabout 10-20 MPH. The composition can protect the eye from stressesresulting from insufficient blinking, e.g., reduced blinking as a resultof staring at an electronic screen for lengthy periods of time.

In an optimally functioning eye, the meibomian gland secretions or sebumare continually deposited on the keratinized portion of the lid marginsof the upper and lower eyelids and moved onto the ocular surface byblinking, lid actions and eye movements. The present composition cansimilarly enter the tear film and lipid layer once administered to theexternal eyelid surface. Thus, the composition can replicate thefunction and efficacy of natural secretions typically supplied to theeye from an optimally functionally meibomian gland upon blinking.Further, as the composition can both minimize evaporation and increasethe thickness of the tear film, the composition can support the tearfilm such that it exceeds the protective characteristics and abilitiesof a normal or typical tear film. Thus, the composition can enable theocular surface to better withstand the contemporary demands and stressesof prolonged electronic screen viewing and other visual activitiesassociated with reduced blinking.

In an embodiment, the composition can be administered to the externaleyelid surface by rubbing the composition on the external eyelid surfaceand, thereby, leaving the composition thereon.

As described previously, once disposed on the external eyelid surface,the residue can be moved onto the tear film and lipid layer aspreviously described. Thus, blinking along with lid actions and eyemovements, provide a continuous mechanism for delivering the compositionto the ocular surface to provide continuous protection for the aqueouslayer and minimize evaporation.

Although more of the composition is delivered to the tear film andocular surface during waking hours, it should be understood that thecomposition can continue to protect the ocular surface even while thepatient is asleep. It has been established that although the lids may bephysically shut with the upper eyelid overriding the lower eyelid toensure closure during sleep, the eyelids may not prevent ambient airfrom reaching the tear film. This exposure of the tear film to ambientair during sleep can result in desiccation, compromise to the tissue ofthe ocular surface, discomfort, and difficulty in sleeping. The presenceof the composition protects against evaporation, thus preventingdesiccation and the sequelae. As such, application of the composition tothe external eyelid surface can protect the ocular surfaces for about 10hours to about 24 hours per day.

The composition can provide an extended period of protection for theocular surfaces and neurosensory systems, including the nociceptors. Forexample, the composition can be administered about 1 to 4 times per dayto protect the ocular surfaces for about 10 hours to about 24 hours perday. In an embodiment, the composition can be rubbed on the externaleyelid surface in a back-and-forth motion from 1 to 4 times.

The composition can be provided in any suitable form to facilitatedepositing the composition on the external eyelid surface. Preferably,the composition is provided in a container similar to thatconventionally used for lip balms. For example, the composition can bedispensed from a conventional lip balm dispenser such as a tubularcannister or a small, wide-mouth oval or circular cannister.

In an embodiment, the composition is configured as a cylindrical bar orstick and provided in a tubular cannister to facilitate application ofthe composition directly on the external eyelid surface. A diameter ofthe cylindrical bar or stick can be about 9-17 mm and, in anotherembodiment, 13-15 mm. In an embodiment, the composition can be rubbed onclosed eyelids by moving the tubular cannister back-and-forth motionacross the entire width of the eyelids, starting on the side of each lidclosest to the nose. One application or dose of the composition caninclude administering the composition by moving the cannister 2 to 4times back and forth across the entire width of the eyelid. Thistechnique is effective in delivering the treatment composition to theeyelids, eyelashes and eyelid margins. The composition can be applied inthis manner 1 to 4 times per day.

In an embodiment, the composition can include from about 20% to about45% beeswax, from about 20% to about 45% jojoba oil, from about 0% toabout 16% shea butter, from about 8% to about 10% caprylic/caprictriglyceride, from about 1% to about 2% phospholipid, from about 0.01%to about 0.02% sodium hyaluronate, and from about 0% to about 16%coconut oil.

In an embodiment, the composition can include about 40% beeswax, about35% jojoba oil, about 15% shea butter, about 8.99% caprylic/caprictriglyceride, about 1.00% phospholipid, and about 0.01% sodiumhyaluronate.

In an embodiment, the composition can include about 37% beeswax, about36% jojoba oil, about 16% shea butter, about 9.99% caprylic/caprictriglyceride, about 1.00% phospholipid, and about 0.01% sodiumhyaluronate.

In an embodiment, the composition can include about 37% beeswax, about36% jojoba oil, about 9.99% caprylic/capric triglyceride, about 1.00%phospholipid, about 0.01% sodium hyaluronate, and about 16.0% coconutoil.

In an embodiment, the composition can include about 37% beeswax, about36% jojoba oil, about 8% shea butter, about 9.99% caprylic/caprictriglyceride, about 1.00% phospholipid, about 0.01% sodium hyaluronate,and about 8.0% coconut oil.

In an embodiment, the composition can include about 45% beeswax, about45% jojoba oil, and about 10% caprylic/capric triglyceride.

In an embodiment, the composition can include about 45% beeswax, about45% jojoba oil, and about 10% coconut oil.

In an embodiment, the composition can include about 45% beeswax, about45% jojoba oil, and about 10% shea butter.

In an embodiment, the composition can include about 30% beeswax, about30% jojoba oil, about 13% shea butter, about 15% caprylic/caprictriglyceride, and about 16% coconut oil.

In an embodiment, the composition can include about 30% beeswax, about30% jojoba oil, about 16% shea butter, about 8% caprylic/caprictriglyceride, and about 16% coconut oil.

In an embodiment, the composition can include about 25% beeswax, about25% jojoba oil, about 20% shea butter, about 15% caprylic/caprictriglyceride, and about 15% coconut oil.

In an embodiment, the composition can include about 20% beeswax, about20% jojoba oil, about 20% shea butter, about 20% caprylic/caprictriglyceride, and about 20% coconut oil.

An applicator or delivery system for treating or preventing anophthalmologic condition in a patient can include a package and anocular treatment composition placed in the package. The ocular treatmentcomposition in the package can be in semi-solid form when in the packageand can liquefy when in contact with the external eyelid surface of thepatient. In a preferred embodiment, the semi-solid composition is in theform of a generally cylindrical bar or stick and the package is atubular cannister having a mechanism, e.g., a twistable knob or pushmechanism at a bottom end thereof, that is configured to raise or lowerthe semi-solid composition as desired. However, other packageconfigurations, utilizing other methods of product application, likejars, tubes, bottles, aerosols, or pouches, in which the oculartreatment composition could be placed and from which the patient couldapply the composition would also be acceptable. The package can beconfigured for single or multiple per-day administration to the patient.

The package can include an outer container, a first product container,and a second product container within the outer container. The firstproduct container can include the ocular treatment composition and thesecond product container can include a surface for labeling andfacilitate product display and handling. The outer container can includean item selected from the group consisting of a single bar code, asingle new drug code, and a single universal product code.

The ocular treatment composition can include from about 37% to about 43%beeswax; from about 33% to about 41% jojoba oil; and at least oneingredient selected from the group consisting of shea butter,caprylic/capric triglyceride, phospholipid, sodium hyaluronate, andcoconut oil.

With subconscious blinking, minute, e.g., nanoliter or microliteramounts, of the composition can move from the eyelid surface to theeyelid margins and then across the eyelid margins to the fluid menisciwhere the tear film is effectively attached to the lower and uppereyelids. Blinking then distributes and mixes the composition into theappropriate layers of the tear film. The more forceful the blink, thegreater the amount of composition delivered. Blinking is primarilysubconscious but may be conscious. Forceful blinking may also be eitherconscious or subconscious depending upon the individual circumstances.

The desired therapeutic response of treatment with the composition is toincrease the protection provided by the tear film to the ocular surfacesand corneal nociceptors most noticeably during the waking hours bychanging the chemical composition and structure of the tear film by theuse of a reservoir feed system to deliver the desired chemicalconstituents to the tear film and ocular surfaces without creatingblurring of vision. The composition has the potential to fortify orenhance the lipid layer and the tear film to exceed the protectivecharacteristics and abilities of a normal or typical tear film, thusenabling the ocular surface to better withstand the contemporary demandsand stresses of prolonged electronic screen viewing and other visualactivities associated with reduced blinking.

Increased protection of the ocular surface following administration ofthe composition has been demonstrated by interferometric measurementsdescribed herein, by an improvement in patient comfort, and by animprovement in stare time. Administration of the composition can provideimmediate relief, delayed relief, sustained relief, or a combinationthereof. The composition can be storage stable, e.g., remain homogeneouswith no signs of separation or discoloration, for at least six monthsfrom time of manufacture.

The compositions described herein may be regulated as a cosmetic, drug,device, medicament, or combinations thereof. In an embodiment, thecompositions can serve as a vehicle for delivering one or more drugactive agents. The one or more drug active agents can include an activepharmaceutical ingredient for bringing about a therapeutic effect to theeye. Accordingly, an embodiment is directed to a pharmaceuticalcomposition comprising the ocular treatment composition and at least oneophthalmologically or pharmacologically acceptable drug active agent.

The present teachings are illustrated by the following examples.

EXAMPLES Example 1 Exemplary Compositions

Tables 1 and 2 provide components of exemplary compositions that wereprepared.

!TABLE 1 Exemplary Composition 1 2 3 4 5 Ingredients % W/W % W/W % W/W %W/W % W/W White Beeswax 40.0 37.0 37.0 37.0 45.0 Jojoba oil 35.0 36.036.0 36.0 45.0 Shea Butter 15.0 16.0 — 8.00 — Caprylic/Capric 8.99 9.999.99 9.99 10.0 Triglyceride Phospholipid 1.00 1.00 1.00 1.00 — Sodium0.01 0.01 0.01 0.01 — Hyaluronate Coconut Oil — — 16.0 8.00 — To Make100.0 100.0 100.0 100.0 100.0 *Penetrometer — — — 4.28 5.41 Results(lb.) *As measured on a Facchini (48011 ALFONSINE, Italy) Penetrometer.

TABLE 2 Exemplary Composition 6 7 8 9 10 11 Ingredients % W/W % W/W %W/W % W/W % W/W % W/W White Beeswax 45.0 45.0 30.0 30.0 25.0 20.0 Jojobaoil 45.0 45.0 30.0 30.0 25.0 20.0 Shea Butter — 10.0 13.0 16.00 20.0020.0 Caprylic/Capric — — 15.0 8.00 15.0 20.0 Triglyceride Phospholipid —— — — — — Sodium — — — — — — Hyaluronate Coconut Oil 10.0 — 12.0 16.0015.00 20.0 To Make 100.0 100.0 100.0 100.0 100.0 100.0 Penetrometer 5.617.02 3.80 3.74 2.93 1.49 Results (lb.)

Exemplary Composition 4 was prepared by combining the white beeswax,jojoba oil, shea butter, caprylic/capric triglyceride, and coconut oilin a suitable vessel to form a mixture. The mixture was slowly warmed to65-70° C. Mixing was initiated once the composition became fluid. Oncethe composition appeared homogeneous, and while mixing, the temperaturewas increased to 70-75° C., and the phospholipid was slowly added. Whilemaintaining the temperature between 70 and 75° C., mixing was continueduntil the phospholipid was uniformly dispersed, and the composition washomogeneous in appearance. While maintaining the temperature between 70and 75° C., the sodium hyaluronate was added and mixing continued untilthe sodium hyaluronate was uniformly dispersed and the composition washomogeneous in appearance. While mixing, the composition was allowed tocool to 67-70° C. The composition was disposed in containers whilemaintaining the temperature of the composition at 67-70° C.

Firmness of Exemplary Compositions 4 and 5 was measured using a Facchini(48011 ALFONSINE, Italy) Penetrometer. Test batches were prepared asdescribed above. While liquid (70-75° C.) approximately 50 grams of testbatch were poured into a 2 fl. oz. PP jar. The samples were allowed tocool (solidify) in an ambient environment. Once cooled (approximately 20minutes), a cap was applied, and the samples were permitted to stand atambient temperature for 24-48 hrs. before testing.

To test the firmness of the samples, the test samples were placed in aconstant temperature (25° C.) bath. After 30 minutes, the sample to betested was removed from the bath and placed on the laboratorycountertop. The cap was removed. Holding the jar firmly on thelaboratory countertop with the left hand, the Facchini Penetrometer washeld between thumb and forefinger of the right hand, pushbutton-commanded indicator hand, the plunger was placed against thesample surface and pressed with increasing pressure until the plungertip slowly penetrated into the sample up to the notch. The FacchiniPenetrometer was removed and measurements from the “lb” scale wererecorded. The plunger was thoroughly cleaned, and repeat measurementswere taken at least 2 more times. The average measurement was reported.

Exemplary Compositions 1-3 and 5-11 were prepared in a manner similar tothe method described for preparing Exemplary Composition 4, with slightadjustments to temperature, ingredients, and/or order of addition ofingredients. Thus, one of ordinary skill in the art would be able toprepare Exemplary Compositions 1-3 and 5-11 based on the descriptionprovided herein for Exemplary Compositions 4.

Example 2 Ocular Film Evaluation

The effectiveness of the composition identified as ExemplaryCompositions 4 in Table 1 in improving the ocular film was evaluated inthe clinical environment on consenting human subjects by a licensed,experienced clinician and compared to the effectiveness of acommercially available control. The study also recorded each subject'sperceptions of eye comfort and blurring of vision. For convenience, thespecific ingredients of the exemplary composition tested (ExemplaryCompositions 4) is provided in Table 3 below.

TABLE 3 Ingredients* % W/W Beeswax 37.0 Simmondsia Chinensis (Jojoba)Seed Oil 36.0 Butyrospermum Parkii (Shea) Butter 8.0 Cocos Nucifera(Coconut) Oil 8.0 Caprylic/Capric Triglyceride 9.99 Lecithin 1.0 SodiumHyaluronate 0.01 Total 100.00 *PCPC's INCI Dictionary Nomenclature

The control used in the evaluation was Retaine MGD by OCuSoft, Inc.(Active ingredients: light mineral oil 0.5% and mineral oil 0.5%;Inactive Ingredients: Cetalkonium chloride, glycerol, poloxamer 188,tris hydrochloride, tromethamine, tyloxapol, and water for injection).

Each subject was diagnosed to have clinically significant dry eyesyndrome. The lipid layer thickness (LLT) and eye comfort level of eachsubject was also determined. Only subjects presenting with a LLT of ≤55nm and a comfort score not greater than “C” at the time of studyinitiation were permitted to participate in the study. Subjects wereinstructed not to use another eye treatment product during the testperiod.

Each product was applied as intended. For the Control, 2 drops wereinstilled into the left eye ocular sac created by distending the lowerlid. Exemplary Composition 4 was packaged in a lip or balm stick typecontainer and applied to the closed eyelids of the right eye using aback-and-forth motion across the entire width of the eyelids. This studyutilized 4 back-and-forth applications starting close to the nose andmoving across the entire eyelid. Additional or repeat application of thetest products were not permitted during the study.

Each product was measured for lipid layer thickness (LLT) and eyecomfort. LLT was measured in nanometers with a LipiView® Ocular SurfaceInterferometer (TearScience, Morrisville, N.C.) which measures LLT byanalyzing the interferometric color changes during the test period.

Eye comfort was reported by the subject using a sliding scale whichdescribed the subject's comfort level. Symptoms were rated using thescale provided in Table 4 below.

TABLE 4 Eye Comfort Scale Uncom- fortable Both- Satisfactory-(irritating ersome Comfortable but does (irritating Intolerable (notoptimal not and (unable to No but not interfere interferes performProblems uncom- with my with my daily Symptoms Optimal fortable) day) myday) tasks) Grade A B C D F

Subjects were also requested to report if any blurring of visionoccurred during the test period. Data were collected 0, 0.25, 0.5, 1, 2,4, 6 and 24 hours after application.

Results

LLT and Eye Comfort results are presented in Table 5 below. No blurringwas reported by subjects for either product during the test.

TABLE 5 Subject 1 Subject 2 Exemplary Exemplary Composition 4 ControlComposition 4 Control Right Left Right Left Right Eye Left Eye Right EyeLeft Eye Time Eye Com- Eye Com- Eye Com- Eye Com- (Hr.) LLT fort LLTfort LLT fort LLT fort 0 47 D   51 D+ 53 D+ 48 D+ 0.25 55 D+ 77 C   56D+ 64 C   0.5 72 C   64 C+ 64 C− 71 B− 1 82 C+ 54 B− 76 B− 58 B− 2≥100    B   47 B− ≥100    B− 51 C   4 92 B+ 49 C− ≥100    B+ 42 D+ 6≥100    B+ 42 D+ 96 A− 46 D+ 24 68 C+ 48 D+ 77 B− 45 D+

DISCUSSION

For both subjects, LLT was improved at the first 15-minute evaluation.The control formula evidenced greater improvement than ExemplaryComposition 4 at the 15- and 30-minute evaluations. This was expected,since the control eyedrop formula containing lipids is applied directlyto the tear film, while the exemplary formula requires an initial“loading” time to reach the tear film.

At the 1-hour evaluation, the LLT for the control formula regressedtoward baseline, while the LLT for Exemplary Composition 4 increased forboth subjects. This was again expected since the control product filmwould be washed out and diluted by normal ocular activities, whereas theExemplary Composition 4 film would continue to generate a thicker film,resist wash out, and initiate creation of a reservoir from whichsustained benefits would be delivered.

At the 2-hour evaluation, the LLT for the control formula had regressedto baseline, while the LLT for Exemplary Composition 4 increased morethan the capability of the instrument to measure for both subjects.(≥100 nm).

At the 4 and 6-hour evaluations, the LLT for the control formula hadregressed to below baseline values, as might be expected, since LLTdecreases over the course of the waking hours. The LLT for ExemplaryComposition 4 remained at a high level, measuring 95 nm to ≥100 nm forboth subjects.

At the 24-hour evaluation, the control formula LLT results for bothsubjects were essentially the same as the baseline values prior to thestart of study, as were the comfort scores. Data show both LLT andcomfort grades were not significantly improved by the control formula 24hours after application.

At the 24-hour evaluation, Exemplary Composition 4 LLT results for bothsubjects were significantly better than baseline, exhibiting an increasein film formation and film substantivity. Comfort scores for bothsubjects had also demonstrated clinical improvement.

Conclusion

Exemplary Composition 4 yielded improvement in ocular film functionalityand subject comfort over the 24-hour test period. Clinical evaluationalso confirmed that the subject's dry eye condition improved. ExemplaryComposition 4 also demonstrated continuous film formation andimprovement in the subjects' eye comfort as a sustained effect whencompared to a commercial product control tested in parallel.

Example 3 Stare Time Assessment

The effectiveness of the composition identified as Exemplary Composition4 in Table 1 in improving stare times was evaluated in the clinicalenvironment on consenting human subjects by a licensed, experiencedclinician and compared to the effectiveness of a commercially availablecontrol. The test room was maintained at a relative humidity level of30% to 40%. Subjects were instructed as to the purpose of the stare timetest, the plan of the study, and the necessity to maintain fixation atthe target object. Subjects were advised that each eye would be treated.The subject was seated and asked to look at a target object 2 to 6 feetfrom the eyes at or not more than 30 degrees below eye level. Subjectswere instructed to shut their eyes down fully, but not to squeeze and,after opening, to stare at the target object for as long as possiblewithout blinking. A computer screen displaying an object for fixationwas utilized. The examiner provided an approximate 30-60 second restperiod and then instructed the subject to shut the eyelids fully andstare at the target until forced to blink. A stopwatch was used tomeasure the stare time in seconds. A stare time ≤7 seconds was requiredto be admitted to the study. The test product, Exemplary Composition 4,was used on the right eye of both subjects, and the commercial producton the left. The commercial product tested was Retaine MGD. The testevaluated the treatments effects initially (time zero) and then at 1, 3and 5 hours thereafter. Eye comfort was reported by the subject usingthe sliding scale shown in Table 4.

The results are provided in tabular form as follows:

TABLE 6 SUBJECT 3 SUBJECT 4 Example 4 Control Example 4 Control StareStare Stare Stare time time time time Hour (sec) Comfort Hour (sec)Comfort Hour (sec) Comfort Hour (sec) Comfort Zero 6 D Zero 5 D Zero 7 DZero 6 D 1 11 C 1 6 D 1 13 D 1 8 D 3 22 B 3 4 D 3 18 B 3 5 D 5 19 B 5 4D 5 21 B 5 7 D

DISCUSSION

When the tear film is inadequate or compromised, blinking occurs torestore the tear film and to provide protection for the neuro sensorysystem of the ocular surface. While the number of blinks and the timebetween blinks varies across patients, the length of time one stareswithout blinking can be measured. The length of time one stares is ametric to evaluate a patient's dry eye condition.

The time between blinks is termed the interblink interval (IBI). It isapproximately 2.5 seconds for those with dry eye and approximately 6seconds for those without dry eye. (Johnston et al, 2013).

Another metric to evaluate dry eye is the length of time thatparticipants can keep their eyes open, referred to as the maximum blinkinterval (MBI). This test was developed to seek “a simple useful testfor dry eye to minimize dependence upon dedicated reagents andmachines”. The MBI is approximately 10 seconds for those with dry eyeand 24 seconds for those without dry eye.

An ocular dry eye treatment composition should increase both theinterblink interval and the maximum blink interval. Increasing theseintervals is evidence of increased protection for the ocular surfacesand the related neuro sensory system and a measurement of treatmentefficacy. The longer the stare time, the less the stress on the tearfilm, the ocular surface and related neuro sensory system, resulting inincreased eye comfort. The term stress time refers to the length of timea subject can stare without blinking from both the scientific andclinical aspects.

The study of stare time with Subject 3 and Subject 4 was conducted withthe exemplary composition (Exemplary Composition 4) and a control, acommercially available dry eye product, Retaine MGD (formulae providedherein).

Conclusion

Exemplary Composition 4 yielded approximately 2.5 to 3.0 timesimprovement in stare time and tear film functionality over the 5-hourtest period, when compared to a commercial product. Eye comfort improvedfrom bothersome-irritating to satisfactory-comfortable over the 5-hourtest period when compared to a commercial product.

The present subject matter being thus described, it will be apparentthat the same may be modified or varied in many ways. Such modificationsand variations are not to be regarded as a departure from the spirit andscope of the present subject matter, and all such modifications andvariations are intended to be included within the scope of the followingclaims.

We claim:
 1. An ocular treatment composition, comprising at least about37% beeswax; at least about 36% jojoba oil; and at least one ingredientselected from the group consisting of shea butter, caprylic/caprictriglyceride, phospholipid, sodium hyaluronate, and coconut oil, whereinthe composition is substantially water-free, and wherein the compositionis non-fluid at room temperature and liquefies when contacted with theskin at body temperatures.
 2. The composition of claim 1, wherein thecomposition comprises about 37% beeswax, about 36% jojoba oil, about 16%shea butter, about 9.99% caprylic/capric triglyceride, about 1.00%phospholipid, and about 0.01% sodium hyaluronate.
 3. The composition ofclaim 1, wherein the composition comprises about 37% beeswax, about 36%jojoba oil, about 9.99% caprylic/capric triglyceride, about 1.00%phospholipid, about 0.01% sodium hyaluronate, and about 16.0% coconutoil.
 4. The composition of claim 1, wherein the composition comprisesabout 37% beeswax, about 36% jojoba oil, about 8% shea butter, about9.99% caprylic/capric triglyceride, about 1.00% phospholipid, about0.01% sodium hyaluronate, and about 8.0% coconut oil.
 5. The compositionof claim 1, wherein the composition comprises about 45% beeswax, about45% jojoba oil, and about 10% caprylic/capric triglyceride.
 6. Apharmaceutical composition, comprising: the ocular treatment compositionof claim 1; and at least one drug active.
 7. The composition of claim 1,wherein the composition can be storage stable for at least six monthsfrom time of manufacture.
 8. A method of treating an ocular condition ina patient, comprising administering the composition of claim 1 to apatient in need thereof.
 9. The method of claim 8, wherein thecomposition is in semi-solid form and is administered by applying thecomposition to the patient's external eyelid surface, leaving asufficient quantity thereon to function as a reservoir.
 10. The methodof claim 9, wherein the composition is administered without causingblurring to the patient.
 11. The method of claim 9, wherein the methodprovides immediate relief, delayed relief, sustained relief, orcombinations thereof.
 12. The method of claim 9, wherein a patient showsimprovement to the patient's ocular surface as measured by aninterferometer.
 13. A delivery system for treating or protecting from anocular condition in a patient, comprising: a package; an oculartreatment composition in the package which is in semi-solid form andliquefies when in contact with an external eyelid of the patient,wherein the ocular treatment composition is the composition of claim 1,the composition in the package is cylindrical; and the package is atubular cannister having a mechanism to raise or lower the compositionin the cannister.
 14. The delivery system according to claim 13, whereinthe composition in the package is useful for single or multiple per-dayadministration to the patient.
 15. The delivery system of claim 13,wherein the package comprises: an outer container; and a first productcontainer and a second product container within the outer container,wherein the first product container includes the ocular treatmentcomposition; and the second product container includes a surface forlabeling.
 16. The delivery system according to claim 15, wherein theouter container includes an item selected from the group consisting of asingle bar code, a single new drug code and a single universal productcode.